Pharmaceutical compositions

ABSTRACT

A pharmaceutical composition in the form of a solid dispersion comprising a macrolide, e.g. a rapamycin or an ascomycin, and a carrier medium.

BACKGROUND AND SUMMARY

This invention relates to oral pharmaceutical compositions comprising amacrolide, e.g. a rapamycin or an ascomycin, in a solid dispersion.

Rapamycin is an immunosuppressive lactam macrolide produceable, forexample by Streptomyces hygroscopicus. The structure of rapamycin isgiven in Kesseler, H., et al.; 1993; Helv. Chim. Acta; 76: 117.Rapamycin is an extremely potent immunosuppressant and has also beenshown to have antitumor and antifungal activity. Its utility as apharmaceutical, however, is restricted by its very low and variablebioavailability. Moreover, rapamycin is highly insoluble in aqueousmedia, e.g. water, making it difficult to formulate stable galeniccompositions. Numerous derivatives of rapamycin are known. Certain16-O-substituted rapamycins are disclosed in WO 94/02136, the contentsof which are incorporated herein by reference. 40-O-substitutedrapamycins are described in, e.g., in U.S. Pat. No. 5,258,389 and WO94/09010 (O-aryl and O-alkyl rapamycins); WO 92/05179 (carboxylic acidesters), U.S. Pat. No. 5,118,677 (amide esters), U.S. Pat. No. 5,118,678(carbamates), U.S. Pat. No. 5,100,883 (fluorinated esters), U.S. Pat.No. 5,151,413 (acetals), U.S. Pat. No. 5,120,842 (silyl ethers), WO93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxyderivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives) all ofwhich are incorporated herein by reference. 32-O-dihydro or substitutedrapamycin are described, e.g., in U.S. Pat. No. 5,256,790, incorporatedherein by reference.

Further rapamycin derivatives are described in PCT application numberEP96/02441, for example 32-deoxorapamycin as described in Example 1, and16-pent-2-ynyloxy-32(S)-dihydrorapamycin as described in Examples 2 and3. The contents of PCT application number EP96/02441 are incorporatedherein by reference.

Rapamycin and its structurally similar analogues and derivatives aretermed collectively herein as “rapamycins”.

On oral administration to humans, solid rapamycins, e.g. rapamycin, maynot be absorbed to any significant extent into the bloodstream. Simplemixtures are known for rapamycins, e.g. rapamycin, with conventionalpharmaceutical excipients; however, disadvantages encountered with thesecompositions include unpredictable dissolution rates, irregularbioavailability profiles, and instability. To date there is noconveniently administrable oral solid formulation available forrapamycin or a derivative thereof.

Accordingly, in one aspect, this invention provides a pharmaceuticalcomposition in the form of a solid dispersion comprising a rapamycin anda carrier medium.

The compositions of this invention provide a high bioavailability ofdrug substance, are convenient to administer, and are stable.

The rapamycin used in the compositions of this invention may be anyrapamycin or derivative thereof, for example as disclosed above or inthe above-mentioned patent applications.

Thus the rapamycin used in the solid dispersion compositions of thisinvention may be rapamycin or an O-substituted derivative in which thehydroxyl group on the cyclohexyl ring of rapamycin is replaced by —OR₁,in which R₁ is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl andaminoalkyl; e.g. as described in WO94/09010, for example40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin and40-O-(2-acetaminoethyl)-rapamycin. The rapamycin derivative may be a 26-or 28-substituted derivative.

Preferred rapamycins for use in the solid dispersion compositionsof-this invention include rapamycin, 40-O-(2-hydroxy)ethyl rapamycin,32-deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin. A morepreferred rapamycin is 40-O-(2-hydroxy)ethyl rapamycin (hereinafterreferred to as compound X).

Numbering of rapamycin derivatives as used herein refers to thestructure disclosed as Formula A at page 4 of published PCT applicationWO 96/13273, the contents of which are incorporated herein by reference.

The term solid dispersion as used herein is understood to mean aco-precipitate of the rapamycin, e.g. 40-O-(2-hydroxy)ethyl rapamycin orrapamycin, with the carrier medium. In the solid dispersion, therapamycin is in amorphous or substantially amorphous form and isphysically bound to the carrier medium.

Compositions of this invention may be administered in any convenientform, for example tablet, capsule, granule or powder form, e.g. in asachet.

The rapamycin may be present in the composition in an amount of about0.01 to about 30-weight-% based on the weight of the composition (%w/w), and preferably in an amount of 1 to 20% w/w based on the totalweight of the composition.

The carrier medium is present in an amount of up to 99.99% by weight,for example 10 to 95 wt-%, based on the total weight of the composition.

In one-embodiment the carrier medium comprises a water-soluble polymer,preferably a cellulose derivative such as hydroxypropylmethylcellulose(HPMC), hydroxypropylmethylcellulose phthalate, or polyvinylpyrrrolidone(PVP). Good results may be obtained using HPMC with a low apparentdynamic viscosity, e.g. below 100 cps as measured at 20° C. for a 2% byweight aqueous solution, e.g below 50 cps, preferably below 20 cps, forexample HPMC 3 cps. HPMC is well-known and described, for example, inthe Handbook of Pharmaceutical Excipients, Second Edition, pub.Pharmaceutical Society of Great Britain and American PharmaceuticalAssociation, 1994, p. 229 to 232, the contents of which are incorporatedherein by reference. HPMC, including HPMC 3 cps, is availablecommercially under the trade name Pharmacoat 603 from the Shinetsucompany.

PVP is available, for example, under the name Povidone (Handbook ofPharmaceutical Excipients), and a PVP having an average molecular weightbetween about 8,000 and about 50,000 Daltons is preferred.

In another embodiment the carrier medium compriseshydroxypropylcellulose (HPC) or a derivative thereof. Examples of HPCderivatives include those having low dynamic viscosity in aqueous media,e.g. water, e.g below about 400 cps, e.g below 150 cps as measured in a2% aqueous solution at 25° C. Preferred HPC derivatives have a lowdegree of substitution, and an average molecular weight below about200,000 Daltons, e.g. between 50,000 and 150, 000 Daltons. Examples ofHPC available commercially include Klucel LF, Klucel EF and Klucel JFfrom the Aqualon company; and Nisso HPC-L available from Nippon SodaLtd;

-   -   a polyethylene glycol (PEG). Examples include PEGs having an        average molecular weight between 1000 and 9000 Daltons, e.g.        between about 1800 and 7000, for example PEG 2000, PEG 4000 or        PEG 6000 (Handbook of Pharmaceutical Excipients);    -   a saturated polyglycolised glyceride, available for example        under the trade mark Gelucir, e.g. Gelucir 44/14, 53/10, 50/13,        42/12, or 35/10 from the Gattefosse company; or    -   a cyclodextrin, for example a P-cyclodextrin or an        x-cyclodextrin. Examples of suitable β-cyclodextrins include        methyl-β-cyclodextrin; dimethyl-β-cyclodextrin;        hydroxypropyl-β-cyclodextrin; glycosyl-β-cyclodextrin;        maltosyl-β-cyclodextrin; sulfo-β-cyclodextrin; sulfo-alkylethers        of β-cyclodextrin, e.g. sulfo-C₁₋₄-alkyl ethers. Examples of        α-cyclodextrins include glucosyl-α-cyclodextrin and        maltosyl-α-cyclodextrin.

The carrier medium may further comprise a water-soluble orwater-insoluble saccharose or other acceptable carrier or filler such aslactose, or microcrystalline cellulose. The filler, if present, isgenerally in an amount of up to about 30% by weight, e.g. 0.5 to 20wt-%, preferably, from about 5 to about 15% by weight of thecomposition. Microcrystalline cellulose is available commercially underthe trade name Avicel, for example from FMC Corporation.

The carrier medium may further comprise one or more surfactants, forexample a non-ionic, ionic, anionic or amphoteric surfactant. Examplesof suitable surfactants include

-   -   polyoxyethylene-polyoxypropylene co-polymers and block        co-polymers known, for example, under the trade names Pluronic        or Poloxamer, e.g. as described in Fiedler, H. P. “Lexikon der        Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete”,        Editio Cantor, D-7960 Aulendorf, 3rd revised and expanded        edition (1989), the contents of which are hereby incorporated by        reference. A preferred polyoxyethylene-polyoxypropylene block        polymer is Poloxamer 188 available from the BASF company;    -   ethoxylated cholesterins known, for example, under the trade        name Solulan, for example Solulan C24 commercially available        from the Amerchol company;    -   vitamin derivatives, e.g. vitamin E derivatives such as        tocopherol polyethylene glycol succinate (TPGS) available from        the Eastman company;    -   sodium dodecylsulfate or sodium laurylsulfate;    -   a bile acid or salt thereof, for example cholic acid, glycolic        acid or a salt, e.g. sodium cholate; or    -   lecithin.

If present in the compositions of this invention, the surfactant(s) isgenerally in an amount of up to about 20%, for example 1 to 15% byweight.

One or more disintegrants may be included in the compositions of thisinvention. Examples of disintegrants include Polyplasdone (Handbook ofPharmaceutical Excipients) available commercially from the ISP company;sodium starch glycolate available commercially from the Generichemcompany; and crosscarmelose sodium available under the trade markAc-di-sol from FMC Corporation. One or more lubricants, for examplemagnesium stearate or colloidal silicon dioxide, may further be includedin the composition of this invention in an amount of up to about 5weight %, e.g. 0.5 to 2 wt-%, based on the weight of the composition.

It may be advantageous to include one or more flavouring agents in thecompositions of this invention.

The present applicants have obtained good results using surfactant-freerapamycin compositions. In another aspect, therefore, this inventionprovides a surfactant-free solid dispersion composition comprising arapamycin as described herein.

Antioxidants and/or stabilisers may be included in the compositions ofthis invention in an amount of up to about 1% by weight, for examplebetween 0.05 and 0.5% by weight. Examples of antioxidants includebutylated hydroxytoluene, DL-α-tocopherol, propyl gallate, ascobylpalmitate and fumaric acid. Malonic acid is an appropriate stabiliser.

In one embodiment of this invention, the composition comprises up to 30%by weight, e.g. 1 to 20 wt-%, 40-O-(2-hydroxy)ethyl rapamycin, and up to95%, e.g. 30 to 90%, HPMC by weight.

The weight ratio of the rapamycin to carrier medium in the compositionsof this invention is generally no more than 1:3, preferably less than1:4.

In another aspect, this invention provides a process for preparing asolid dispersion composition as described herein.

In one embodiment the compositions of this invention may be obtained bydissolving or suspending the rapamycin and carrier medium in a solventor solvent mixture. The solvent may be a single solvent or mixture ofsolvents, and the order of dissolution and suspension of the rapamycinwith the carrier medium in the solvent may be varied. Solvents suitablefor use in preparing solid dispersion compositions of this invention maybe organic solvents such as an alcohol, for example methanol, ethanol,or isopropanol; an ester, e.g. ethylacetate; an ether, e.g. diethylether, a ketone, e.g. acetone; or a halogenated hydrocarbon, e.g.dichloroethane. A convenient solvent mixture is an ethanol/acetonemixture having a weight ratio of ethanol to acetone of between about1:10 to about 10:1, for example 1:5 to 5:1.

Typically the rapamycin and carrier medium are present in a ratio byweight with the solvent of 1:0.1 to 1:20. The solvent may be evaporatedand the rapamycin co-precipitated with carrier medium. The resultingresidue may be dried, for example under reduced pressure, sieved andmilled. The milled dispersion may be combined with other excipients and,for example, compressed as a tablet, or filled into sachets or gelatincapsules.

In another embodiment, the solid dispersion compositions may be preparedby melting the carrier medium to form a melt, and combining the meltwith the rapamycin, e.g. by stirring, optionally in the presence of asolvent or solvent mixture as described herein.

Alternatively the solid dispersions of this invention may be prepared byspray drying techniques as described, for example, in Theory andPractice of Industrial Pharmacy, Lachmann et al., 1986. A suspension asformed above is dispersed through a nozzle into a chamber maintained at,for example, 20 to 80° C. The solvent is evaporated on passing throughthe nozzle, and finely dispersed particles are collected.

The compositions of this invention, after milling, typically have a meanparticle size of less than about 0.5 mm, for example less than about 350μm, e.g. about 100 to about 300 μm.

The oral compositions of this invention are useful for the knownindications of the rapamycin, e.g. the following conditions:

-   -   a) Treatment and prevention of organ or tissue allo- or        xeno-transplant rejection, e.g. for the treatment of recipients        of e.g. heart, lung, combined heart-lung, liver, kidney,        pancreatic, skin or corneal transplants. They are also indicated        for the prevention of graft-versus-host disease, such as        following bone marrow transplantation.    -   b) Treatment and prevention of autoimmune disease and of        inflammatory conditions, in particular inflammatory conditions        with an etiology including an autoimmune component such as        arthritis (for example rheumatoid arthritis, arthritis chronica        progrediente and arthritis deformans) and rheumatic diseases.        Specific autoimmune diseases for which the compounds of the        invention may be employed include, autoimmune hematological        disorders (including e.g. hemolytic anaemia, aplastic anaemia,        pure red cell anaemia and idiopathic thrombocytopenia), systemic        lupus erythematosus, polychondritis, sclerodoma, Wegener        granulamatosis, dermatomyositis, chronic active hepatitis,        myasthenia gravis, psoriasis, Steven-Johnson syndrome,        idiopathic sprue, autoimmune inflammatory bowel disease        (including e.g. ulcerative colitis and Crohn's disease)        endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple        sclerosis, primary billiary cirrhosis, juvenile diabetes        (diabetes mellitus type I), uveitis (anterior and posterior),        keratoconjunctivitis sicca and vernal keratoconjunctivitis,        interstitial lung fibrosis, psoriatic arthritis,        glomerulonephritis (with and without nephrotic syndrome, e.g.        including idiopathic nephrotic syndrome or minimal change        nephropathy) and juvenile dermatomyositis.    -   c) Treatment and prevention of asthma    -   d) Treatment of multi-drug resistance (MDR). MDR is particularly        problematic in cancer patients and AIDS patients who will not        respond to conventional chemotherapy because the medication is        pumped out of the cells by Pgp. The compositions are therefore        useful for enhancing the efficacy of other chemotherapeutic        agents in the treatment and control of multidrug resistant        conditions such as multidrug resistant cancer or multidrug        resistant AIDS.    -   e) Treatment of proliferative disorders, e.g. tumors,        hyperproliferative skin disorder and the like.    -   f) Treatment of fungal infections.    -   g) Treatment and prevention of inflammation, especially in        potentiating the action of steroids.    -   h) Treatment and prevention of infection, especially infection        by pathogens having Mip or Mip-like factors.    -   i) Treatment of overdoses of FK-506 and other macrophilin        binding immunosuppressants.

Where the pharmaceutical composition of this invention is in unit dosageform, e.g. as a tablet, capsule, granules or powder, each unit dosagewill suitably contain between 1 mg and 100 mg of the drug substance,more preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg.Such unit dosage forms are suitable for administration 1 to 5 timesdaily depending upon the particular purpose of therapy, the phase oftherapy and the like.

The exact amount of the compositions to be administered depends onseveral factors, for example the desired duration of treatment and therate of release of the rapamycin.

The utility of the pharmaceutical compositions can be observed instandard clinical tests in, for example, known indications of activeagent dosages giving equivalent blood levels of active agent; forexample using dosages in the range of 1 mg to 1000 mg, e.g. 5 mg to 100mg, of active agent per day for a 75 kilogram adult and in standardanimal models. The increased bioavailability of the drug substanceprovided by the compositions can be observed in standard animal testsand in clinical trials.

The dosage form used, e.g. a tablet, may be coated, for example using anenteric coating. Suitable coatings may comprise cellulose acetatephthalate; hydroxypropylmethylcellulose phthalate; a polymethyacrylicacid copolymer, e.g. Eudragit L, S; or hydroxypropylmethylcellulosesuccinate.

The rapamycin used in the compositions of this invention, e.g.40-0-(2-hydroxy)ethyl rapamycin or rapamycin, may be in crystalline oramorphous form prior to formation of the solid dispersion. An advantage,therefore, of this invention is that the rapamycin need not becrystalline. Thus the rapamycin may be used directly in combination, forexample with a solvent, and does not have to be isolated in advance.Another advantage of the invention is that dissolution rates of thesolid dispersion are higher than dissolution rates found for acrystalline rapamycin or an amorphous rapamycin in a simple mixture.

In another aspect, this invention provides a pharmaceutical compositionin the form of a solid dispersion comprising an ascomycin and a carriermedium.

Examples of suitable ascomycins for use in the solid dispersioncompositions of this invention include ascomycin or a derivativethereof, e.g. 33epi-chloro-33-desoxy-ascomycin.

To date there is no conveniently administrable oral solid formulationavailable for 33-epi-chloro-33-desoxy-ascomycin. In another aspect,therefore, this invention provides a pharmaceutical composition in theform of a solid dispersion comprising 33-epi-chloro-33-desoxy-ascomycinand a carrier medium.

The compound 33-epi-chloro-33-desoxy-ascomycin is described in publishedEuropean application EP 427 680 under Example 66a.

33-epi-chloro-33-desoxy-ascomycin will be referred to hereinafter asCompound Y.

The ascomycin, e.g. compound Y, compositions of this invention provide ahigh bioavailability of drug substance, are convenient to administer,and are stable.

The ascomycin, e.g. compound Y, may be present in the composition in anamount of about 0.01 to about 30% w/w, and preferably in an amount of 1to 20% w/w.

The carrier medium may comprise any of the aforementioned components inamounts by wt-% as described above. Suitable water-soluble polymers,cyclodextrins and other excipients, e.g. surfactants, for use in the33-epi-chloro-33-desoxy-ascomycin compositions of this invention are asdescribed above.

In a preferred aspect, this invention provides a surfactant-containingcomposition comprising an ascomycin, e.g. compound Y, in the form of asolid dispersion as described herein.

The weight ratio of the ascomycin, e.g. compound Y, to carrier medium isgenerally no more than 1:3, preferably less than 1:4.

The ascomycin, e.g. compound Y, solid dispersion compositions may beprepared in analogous manner to the processes described above.

The oral compositions of compound Y disclosed herein are useful, forexample, in the treatment of inflammatory and hyperproliferative skindiseases and of cutaneous manifestations of immunologically-mediateddiseases. More specifically, the compositions of this invention areuseful as antiinflammatory and as immunosuppressant andantiproliferative agents for use in the prevention and treatment ofinflammatory conditions and of conditions requiring immunosuppression,such as

-   -   a) the prevention and treatment of        -   rejection of organ or tissue transplantation, e.g. of heart,            kidney, liver, bone marrow and skin, graft-versus-host            disease, such as following bone marrow grafts,        -   autoimmune diseases such as rheumatoid arthritis, systemic            lupus erythematosus, Hashimoto's thyroidis, multiple            sclerosis, Myasthenia gravis, diabetes type I and uveitis,        -   cutaneous manifestations of immunologically-mediated            illnesses;    -   b) the treatment of inflammatory and hyperproliferative skin        diseases, such as psoriasis, atopical dermatitis, contact        dermatitis and further eczematous dermatitises, seborrhoeic        dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid,        Epidermolysis bullosa, urticaria, angioedemas, vasculitides,        erythemas, cutaneous eosinophilias, Lupus erythematosus and        acne; and    -   c) Alopecia areata.

Where the pharmaceutical composition of this invention is in unit dosageform, e.g. as a tablet, capsule or powder, each unit dosage willsuitably contain between 1 mg and 100 mg of the drug substance, morepreferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg. Suchunit dosage forms are suitable for administration 1 to 5 times dailydepending upon the particular purpose of therapy, the phase of therapyand the like.

In one embodiment of this invention, the composition comprises 30% byweight compound Y and 70% by weight HPMC in a dosage of e.g. 10 to 50 mgper day for use in, e.g. psoriasis, atopical dermatitis or contactdermatitis.

The exact amount of the compositions to be administered depends onseveral factors, for example the desired duration of treatment and therate of release of compound Y.

The utility of the pharmaceutical compositions containing compound Y canbe observed in standard clinical tests in, for example, knownindications of active agent dosages giving equivalent blood levels ofactive agent; for example using dosages in the range of 1 mg to 1000 mgof active agent per day for a 75 kilogram adult and in standard animalmodels. The increased bioavailability of the drug substance provided bythe compositions can be observed in standard animal tests and inclinical trials.

Following is a description by way of example only of solid dispersioncompositions of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of mean blood levels of33-epi-chloro-33-desoxy-ascomycin in rats resulting from administrationof Forms E, F and G as described in Examples 7, 8 and 9.

FIG. 2 is a graph of blood levels of 33-epi-chloro-33-desoxy-ascomycinin rats resulting from the administration of Forms E and F, as describedin Examples 7 and 8, when the Forms are with food.

EXAMPLE 1

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 9.1 HPMC 3 cps 81.8 Lactose200 mesh 9.1The composition (Form A) is prepared by dissolving the rapamycin andcarrier medium in an ethanol/acetone mixture. Absolute ethanol is usedin a 1:1 ratio by weight with the acetone. The solvents are thenevaporated, and the resulting dry residue milled to a fine powder withmean particle size <0.5 mm.

EXAMPLE 2

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 16.7 HPMC 3 cps 66.7Poloxamer 188 (from BASF) 16.7The composition (Form B) is prepared in analogous manner to that inExample 1.

EXAMPLE 3

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 16.7 HPMC 3 cps 66.7 TPGS*16.7*tocopherol polyethylene glycol succinateThe composition (Form C) is prepared in analogous manner to that inExample 1.

EXAMPLE 4

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 10 HPMC 3 cps 80 SolulanC24 (from Amerchol) 10The composition (Form D) is prepared in analogous manner to that inExample 1.

The above compositions Forms A to D may be formed into tablets, filledinto capsules, or powdered and packaged in sachets.

EXAMPLE 5 Pharmacokinetics after Administration of 40-O-(2-hydroxy)Ethyl Rapamycin to Rats

a) Drug Administration

0.5 ml aqueous dispersions of the Compound X compositions (correspondingto 4.0 mg active ingredient/rat) were administered by gastric intubationduring a short inhalation anaesthesia with a 1 ml syringe, attached to apolyethylene tube. Six animals were used for each composition Forms A,B, C and D.

b) Blood Sampling

The animals received a permanent cannula into a vena jugularis one dayprior to this experiment. 0.5 ml venous blood (vena jugularis) wascollected from each rat and stored in 2.5 ml EDTA tubes. The bloodsamples of 2 animals (1 and 2, 3 and 4, 5 and 6) were pooled and storedat −80° C. until drug analysis. Samples were taken before administrationand 10 minutes (m), 30 m, 60 m, 120 m, 300 m, 480 m and 1440 m afterdrug administration.

c) Bioanalytics

The blood samples were analysed using reversed phase HPLC.

Table 1 shows the pharmacokinetic data collected after administration ofCompound X to rats. TABLE 1 Summary Profiles (averages of 2-3 pools)blood concentration (ng/ml) time (h) Form A Form B Form C Form D 0 7 7 77 0.17 118 117 85 68 0.5 422 131 125 74 1 375 129 96 66 2 277 82 89 54 5573 92 58 39 8 496 66 45 34 24 93 30 34 30 Cmax (ng/ml) 573 135 131 81Tmax (hr) 5.00 0.50 0.50 0.50 AUC 0-8 h 3502 720 565 376 [(ng/ml).h] AUC0-24 h 8213 1487 1192 886 [(ng/ml).h]Form A resulted in blood levels higher than those after administrationof surfactant-containing compositions.

EXAMPLE 6 Dog Study

Following the above promising results, a relative bioavailability studywas performed in fasted beagle dogs using a dose of 1 mg/kg body weight.Hard gelatin capsules each containing 10 mg compound X were administeredto 8 dogs in a 4-way latin square design; the dogs were fed 6 hours postadministration of the capsules, and blood levels of compound X weredetermined over 48 hours. Similar blood concentration profiles ofcompound X were observed for all the dogs, with a terminal halflife ofcompound X in blood between 10 and 40 hours. Median peak levels of 140ng/ml and median AUC levels of 048 hr ca. 1600 ng.h/ml were observed.

EXAMPLE 7

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 20 HPMC 3 cps 80The composition (Form E) is prepared by dissolving compound Y andcarrier medium in an ethanol/acetone mixture. The solvents are thenevaporated, and the resulting dry residue milled.

EXAMPLE 8

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 20 HPMC 3 cps 70 Poloxamer188 10The composition (Form F) is prepared in analogous manner to that inExample 5.

EXAMPLE 9

A solid dispersion composition is prepared containing the followingingredients (in parts by weight): Compound X 20 HPMC 3 cps 75 Sodiumlaurylsulfate  5The composition (Form G) is prepared in analogous manner to that inExample 7.

The above compositions Forms E to G may be formed into tablets, filledinto capsules, or powdered and packaged in sachets.

EXAMPLE 10 Pharmacokinetics after Administration of33-epi-chloro-33-desoxy-ascomycin to Rats

a) Drug Administration

0.5 ml aqueous dispersions of the drug compositions (corresponding to4.0 mg active ingredient/rat) were administered by gastric intubationduring a short inhalation anaesthesia with a 1 ml syringe, attached to apolyethylene tube. Six animals were used for each composition Forms E,F, and G.

b) Blood Sampling

The animals received a permanent cannula into a vena jugularis one dayprior to this experiment. 0.5 ml venous blood (vena jugularis) wascollected from each rat and stored in 2.5 ml EDTA tubes. The bloodsamples of 2 animals (1 and 2, 3 and 4, 5 and 6) were pooled and storedat −80° C. until drug analysis. Samples were taken before administrationand 10 minutes (m), 30 m, 60 m, 120 m, 300 m, 480 m and 1440 m afterdrug administration.

c) Bioanalytics

The blood samples were analysed using reversed phase HPLC.

The results are plotted in FIGS. 1 and 2, in which ng/ml (vertical axis)is plotted against time in hours (horizontal axis).

FIG. 1 shows that Form F resulted in blood levels substantially higherthan blood levels observed after administration of Form E or Form G.

FIG. 2 shows that Form F resulted in high blood levels when administeredwith food.

Compound Y is in amorphous form in the compositions E, F and G onformation and after 6 months storage as determined by X-ray diffraction.

Forms E, F and G are tested for respective dissolution rates. Onstirring in a solution of 0.2 wt % sodium dodecylsulfate in water at 37°C., it is found that over 80% available compound Y is released anddissolved from each milled composition containing 10 mg compound Y after30 minutes. 92% available compound Y is released from Form E. Thiscompares with approximately 5% release after 30 minutes from anequivalent amount of crystalline compound Y.

1-10. (canceled)
 11. A method of forming a pharmaceutical compositioncomprising 33-epi-chloro-33-desoxy-ascomycin and a carrier mediumwherein the method comprises: (a) suspending the33-epi-chloro-33-desoxy-ascomycin in a solvent to form a suspension, (b)combining one or more carrier components with the solvent, and (c) spraydrying the suspension to form the pharmaceutical composition.